DESCRIPTION: Cyclic nucleotide-gated ion channels were first discovered in retinal rods where they generate the electrical activity of the cell in response to light. Another member of the cyclic nucleotide-gated (CNG) channel family was subsequently discovered in olfactory receptor neurons. In both systems, CNG channels covert stimulus-induced changes in the intracellular levels of cyclic nucleotides into graded changes in the membrane potential, thereby modulating the release of neurotransmitter at the synapse. CNG channels are also found in bipolar and ganglion cells of the retina and in hippocampal neurons where they may modify synaptic strength in response to nitric oxide cues. More recently, CNG channels have been found in tissues throughout the body including the brain, heart, live, kidneys, and testes. The role of the CNG channels in these tissues is more speculative. The lack of specific pharmacological tools has made it difficult to unambiguously determine the physiological role of CNG channels. Specific blockers of voltage-gated sodium, calcium and potassium channels and many ionotropic neurotransmitter receptors are available but blockers for CNG channels are scarce. Recently this investigator purified a novel peptide toxin from the venom of the Australian Brown snake, Pseudechis australis, which blocks current through CNG channels. This toxin, termed Pseudechetoxin (PsTx), is a highly basic 24-kDa protein. When applied to the extracellular face of membrane patches containing the alpha-subunit of the rod channel, PsTx inhibited current with an apparent affinity of 100 nM. It was even more effective at blocking the olfactory version of the CNG channel. The investigator now proposes to study the interaction between PsTx and CNG channels using molecular genetic and electrophysiological methods. It is hoped that PsTx will be a valuable pharmacological tool to discern the function of CNG channels in the retina and throughout the body. These studies aim to provide a better understanding of the physiology of CNG channels in health and disease and will lay a foundation for future endeavors in drug design.